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Microglia-Based Phenotypic Screening Identifies a Novel Inhibitor of Neuroinflammation Effective in Alzheimer's
Wei Zhou1,2, Guifa Zhong1, Sihai Fu3
1State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530, People's Republic of China.
Abstract:
Currently, anti-AD drug discovery using target-based approaches is extremely challenging due to unclear etiology of AD and absence of validated therapeutic protein targets. Neuronal death, regardless of causes, plays a key role in AD progression, and it is directly linked to neuroinflammation. Meanwhile, phenotypic screening is making a resurgence in drug discovery process as an alternative to target-focused approaches. Herein, we employed microglia-based phenotypic screenings to search for small molecules that modulate the release of detrimental proinflammatory cytokines. The identified novel pharmacological inhibitor of neuroinflammation (named GIBH-130) was validated to alter phenotypes of neuroinflammation in AD brains. Notably, this molecule exhibited comparable in vivo efficacy of cognitive impairment relief to donepezil and memantine respectively in both β amyloid-induced and APP/PS1 double transgenic Alzheimer's murine models at a substantially lower dose (0.25 mg/kg). Therefore, GIBH-130 constitutes a unique chemical probe for pathogenesis research and drug development of AD, and it also suggests microglia-based phenotypic screenings that target neuroinflammation as an effective and feasible strategy to identify novel anti-AD agents.
Insights
Researchers discovered GIBH-130, a novel neuroinflammation inhibitor, effective for Alzheimer's disease (AD) treatment. This microglia-based approach offers a promising strategy for developing new anti-AD drugs.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Alzheimer's disease (AD) drug discovery faces challenges due to unclear etiology and lack of validated targets.
- Neuronal death and neuroinflammation are critical in AD progression.
- Phenotypic screening is re-emerging as a viable alternative to target-based drug discovery.
Purpose of the Study:
- To identify small molecules that modulate the release of pro-inflammatory cytokines using microglia-based phenotypic screening.
- To evaluate the efficacy of a novel inhibitor, GIBH-130, in preclinical models of Alzheimer's disease.
Main Methods:
- Employed microglia-based phenotypic screening to identify novel anti-neuroinflammatory compounds.
- Validated the identified inhibitor, GIBH-130, for its ability to alter neuroinflammation phenotypes in AD brain models.
- Assessed the in vivo efficacy of GIBH-130 in ameliorating cognitive impairment in established Alzheimer's murine models.
Main Results:
- Identified GIBH-130, a novel pharmacological inhibitor of neuroinflammation.
- GIBH-130 demonstrated significant efficacy in reducing cognitive impairment in both beta-amyloid-induced and APP/PS1 transgenic Alzheimer's models.
- The molecule showed comparable efficacy to donepezil and memantine at a substantially lower dose (0.25 mg/kg).
Conclusions:
- GIBH-130 serves as a valuable chemical probe for Alzheimer's disease pathogenesis research and therapeutic development.
- Microglia-based phenotypic screening targeting neuroinflammation is an effective strategy for discovering novel anti-Alzheimer's agents.
